Hawthorn fruit extracts alleviate high-fat diet-induced NAFLD by inhibiting ERK and regulating hepatic purine metabolism

Abstract

Intrahepatic fat accumulation is a characteristic of non-alcoholic fatty liver disease (NAFLD), a chronic metabolic liver disease. Hawthorn fruit is a common fruit in East Asia with fat-reducing properties, while its active components and mechanisms of action are still unclear. The purpose of this study was to utilize 70% ethanol for the extraction of hawthorn fruit and to investigate the mechanism and therapeutic impact of hawthorn fruit extracts (HFE) in the treatment of NAFLD. A 12-week high-fat diet was used to establish a NAFLD mouse model, and oleate/palmitate-induced HepG2 cells were used to create a NAFLD cell model. UHPLC-QTOF/MS was employed for both constituent analysis of HFE and metabolomics analysis of the liver. Network pharmacology and molecular docking were used to identify potential targets of HFE for the treatment of NAFLD and to analyze the possible interactions between HFE compounds and targets. A total of 17 primary compounds were identified in HFE. HFE significantly inhibited lipid accumulation in hepatic cells both in vivo and in vitro, and mitigated liver damage. Hepatic metabolomics indicated that HFE notably improved metabolic disorders in NAFLD mice, particularly in the purine metabolism pathway. Integrative analysis combining network pharmacology, molecular docking, and Western blotting demonstrated that HFE primarily targets ERK and effectively suppresses its hyperactivation. Quercetin and rutin, present in HFE, emerged as potential key components, exerting effects through direct binding with ERK1/2. In conclusion, this study found that HFE alleviated NAFLD by inhibiting ERK and regulating hepatic purine metabolism.